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Objectives
• Diagnostic Techniques• Common terminology, definitions in cancer• Multi-step carcinogenesis• Invasion & Metastasis• Tumor grading• Tumor staging• Newer prognostic/predictive testing
http://www.cancer.org
Diagnostic Methods in Tumor Pathology• Histology-morphology– ‘Old fashioned’ microscope,
H &E slides, formalin fixed paraffin embedded (FFPE)
• Immunohistochemistry– Esp. tumor differentiation,
mitotic rate
Undiff. tumor HMB45+ Melanoma
H=hematoxylin, nucleic acids, purple
E=eosin, protein, pink
Diagnostic Methods in Tumor Pathology• Immunohistochemistry– May help subclassify– Rarely, may imply specific
genetic rearrangement
TFE3 +nuclear
Aberrant TFE3 protein expression as a result of t(X;1)(p11.2;q21)
Argani. AJSP 26:1553-66
Pediatric Kidney Cancer
Loss of PMS2 expression, colon cancerMismatch repair protein deficient (Lynch)
Normal
Cancer
Diagnostic Methods in Tumor Pathology
FISH & CytogeneticsCharacteristic
translocations
t(11;22) Ewing’sEWS-FLI1Breakapart FISH probe
(courtesy of Helen Lawce)
Diagnostic Methods in Tumor Pathology• Molecular/PCR– Esp. hematopathology
• T- B-cell clonality• Characteristic mutations
• (Coming: gene arrays, etc)
FISH: Her2 amplification(breast cancer)Courtesy Dana Bangs
PCR/HPLC (WAVE) forC-kit mutations in GISTCorless Am J Pathol. 2002 160:1567-72
Nomenclature• Hypertrophy: increase in size of cells• Hyperplasia: increase in the # of cells in
organ/tissue• Neoplasia: “new growth”– Growth exceeds/uncoordinated with normal tissue– Growth persists after stimulus removed– CLONAL– Benign or malignant– Neoplasm=proliferating cells & associated stroma
Neoplasia: Benign• Cohesive, expansile masses (tumors)• Remain localized– No capacity to invade, metastasize
• Slow growing– Often encapsulated
• Well differentiated (still resemble normal)• Often named with suffix “-oma”
• Chondroma (benign neoplasm of cartilage)• Hemangioma (benign neoplasm of blood vessels)• Leiomyoma (benign neoplasm of smooth muscle)• Adenoma (benign epithelial neoplasm)• Cystadenoma, Papilloma etc
Neoplasia: Malignant• Invade and destroy surrounding tissue• Capacity for metastasis– Spread through blood vessels/lymphatics to distant sites
• Higher rate of growth• Pleomorphism (variation in size/shape)• Abnormal nuclear morphology & hyperchromasia• De-differentiation/Anaplasia• Nomenclature:– Malignant epithelial neoplasm: carcinoma– Malignant mesenchyma: sarcoma– Malignant hematolymphoid: leukemia, lymphoma– Malignant melanocytic: melanoma– Malignant germ cell: seminoma, and others
Neoplasia: Benign vs. MalignantUterus
Robbins 7-22
Normal, Benign, Malignant
Normal colon (lower) & tubular adenoma (benign, upper left)
Normal colon and invasive adenocarcinoma (right, Malignant)
Adenoma, colon (TVA)
Normal, Benign, Malignant
Normal breast
Benign hyperplasia Invasive carcinoma
Histologic Features of Malignant Cells
http://www.usc.edu/hsc/dental/PTHL312abc/312a/05/Reader/reader.html
Transformation• “Malignant change in the target cell”• What features define a transformed cell?
Hanahan and Weinberg.“The Hallmarks of Cancer”Cell. 100:57-70. 2000
And Genomic Instability
Transformation: Darwinian?• “Malignant change in the target cell”
Hanahan and Weinberg.“The Hallmarks of Cancer”Cell. 100:57-70. 2000
Mechanisms & chronology of acquired capabilities vary By organ/tumor type By subtype, etc
“The Genomic Landscapes of
Breast and Colorectal Cancer”
Wood et al. Science. 2007318: 1108-113
“Tumors as Complex Tissues”or, “It takes a village”
Hanahan and Weinberg.“The Hallmarks of Cancer”Cell. 100:57-70. 2000
• Malignant cells that have not yet breached the basement membrane (still confined)
Concept: Carcinoma in situ (CIS)
DCIS: breast
DCIS & invasive
p63
Calponin
Carcinoma In Situ (right) and Invasive carcinoma (left), breast
Carcinoma in situ (CIS)
SquamousCell CIS
Carcinoma in situ (CIS)Carcinoma in situ (CIS)
Squamous CIS
Invasive SCC
Invasion & metastasis1’tumor
Lymph
Platelets
ECM
BM
Robbins 7-42
Colon CA in lymphatic channel
Vein
Vein
Artery
Artery
Tumor growth and spread
Normal cell(Lung)
Single tumor cell
30 doublings
1 gm=109 cellsSmallest clinically detectable mass
10 doublings
1 kg=1012 cellsMaximum mass compatible w/ life
Robbins 7-12Liver mets
Tumor angiogenesis
Robbins 7-41
Leaky vessels
Transformation
• Some benign neoplasms have propensity to acquire additional genetic changes and progress to malignancy (precursors)– Example: colonic adenoma carcinoma
• Others rarely undergo transformation– Example: Uterine leiomyomas, salivary gland
pleomorphic adenomas
Robbins. 7th ed. Figure 17-60
APCAPC-cat
P5318q21SMAD2,4
Telomerases, etcKras
Histologic and Molecular Progression:Histologic and Molecular Progression:ColonColon
LG dysplasia HG dysplasia Carcinoma
It’s never that simple…
http://www.rr-research.no/wcache/650x_58df157ee0b2a665ce8c99e0dd99e435Adenoma_carcinoma.jpg
http://www.mdconsult.com/das/book/body/128522719-2/0/1492/f4-u1.0-B978-1-4160-2805-5..50208-1..gr5.jpg from Cecil Medicine 23 ed (Saunders, Elsevier)
Histologic and molecular progression:Breast
Tissue
Invasion
Robbins Fig 23-15
NormalFlorid
proliferation ADH DCISInfiltratingCarcinoma
True precursor?
Non-obligate precursor?